6533b862fe1ef96bd12c6e94
RESEARCH PRODUCT
Expression of a mutant HSP110 sensitizes colorectal cancer cells to chemotherapy and improves disease prognosis
Kristell WanherdrickKristell WanherdrickAlex DuvalAlex DuvalEmmanuel TiretGérard MilanoOlivier BuhardOlivier BuhardJanick SelvesMarie-christine Etienne-grimaldiChristophe TournigandLeila Bengrine-lefevreSylvain KirzinCarmen GarridoCarmen GarridoGaëtan JegoGaëtan JegoAnaïs LagrangeAnaïs LagrangeEmmanuel TubacherVirginie Penard-lacroniqueYann ParcCoralie DorardHabib ZoualiAurélie De ThonelAurélie De ThonelMagali SvrcekMagali SvrcekChristophe LouvetJérémie H. LefevreMarie-pierre GaubAnne Laure JolyAnne Laure JolyLaetitia MarisaAda ColluraAda ColluraJean-françois FléjouJessica GobboJessica Gobbosubject
Organoplatinum CompoundsColorectal cancermedicine.medical_treatment[SDV]Life Sciences [q-bio]Blotting WesternFluorescent Antibody TechniqueAntineoplastic AgentsBiologyBioinformaticsReal-Time Polymerase Chain ReactionTransfectionGeneral Biochemistry Genetics and Molecular Biology03 medical and health sciences0302 clinical medicineHeat shock proteinCell Line TumormedicineHumansImmunoprecipitationHSP110 Heat-Shock ProteinsneoplasmsCellular localizationComputingMilieux_MISCELLANEOUS030304 developmental biologyDNA Primers0303 health sciencesChemotherapyMicrosatellite instabilityGeneral MedicineTransfectionmedicine.diseasePrognosisdigestive system diseases3. Good healthOxaliplatinOxaliplatin030220 oncology & carcinogenesisCancer cellMutationCancer researchRegression AnalysisMicrosatellite InstabilityFluorouracilColorectal Neoplasmsmedicine.drugPlasmidsdescription
Heat shock proteins (HSPs) are necessary for cancer cell survival. We identified a mutant of HSP110 (HSP110ΔE9) in colorectal cancer showing microsatellite instability (MSI CRC), generated from an aberrantly spliced mRNA and lacking the HSP110 substrate-binding domain. This mutant was expressed at variable levels in almost all MSI CRC cell lines and primary tumors tested. HSP110ΔE9 impaired both the normal cellular localization of HSP110 and its interaction with other HSPs, thus abrogating the chaperone activity and antiapoptotic function of HSP110 in a dominant-negative manner. HSP110ΔE9 overexpression caused the sensitization of cells to anticancer agents such as oxaliplatin and 5-fluorouracil, which are routinely prescribed in the adjuvant treatment of people with CRC. The survival and response to chemotherapy of subjects with MSI CRCs was associated with the tumor expression level of HSP110ΔE9. HSP110 may thus constitute a major determinant for both prognosis and treatment response in CRC.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2011-10-01 |